Alicyclic piperidine derivatives as insect repellents

ABSTRACT

A number of alicyclic carboxamides of the formula ##STR1## wherein n, R 1 , R 2 , and R 3  are defined hereinbelow have been found to be useful insect repellents.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to insect repellents and more particularly to certain novel carboxamides containing an alicyclic moiety and their use as insect repellents.

2. Description of the Prior Art

There is a continuing need for insect repellents or formulations thereof that are significantly more effective or longer lasting than those now in use. All of the repellents now in use for application to the skin have disadvantages, that is, they are not effective for long enough periods of time and are subject to loss by abrasion, evaporation, absorption, and immersion in water. Moreover, all cause a stinging sensation when they contact the eyelids and lips, and are effective only when they are present on the skin or clothing in relatively large quantities. Mosquitoes, sand flies, black flies, stable flies, tsetse flies, gnats, and tabanids are among the many species of biting fly that cause annoyance and distress throughout the world. Many species of biting insects spread human and animal diseases. There are many areas throughout the world in both developed and developing nations where the use of protective clothing and repellents is the only means available to individuals for personal protection. Deet (N,N-diethyl-m-toluamide) has proved to be the most outstanding all-purpose individual repellent yet developed (Proceedings of a Symposium, University of Alberta, Edmonton, Canada, May 16-18, 1972, Defense Research Board, Ottawa, Canada, 1973. DR-217: 109-113). Deet was reported as a promising repellent in 1954 (Journal of Organic Chemistry, 19, 493, 1954). Since that time, no repellent has been reported as being superior to deet as an all-purpose repellent despite a continuing search for such a chemical.

SUMMARY OF THE INVENTION

An object of this invention is to provide a class of compounds that are useful as insect repellents.

The above object is accomplished by a number of novel carboxamides having from about 11 to about 18 carbon atoms and containing an alicyclic moiety. Many of these compounds are more effective than presently available repellents and many are effective against a wide variety of insects.

DESCRIPTION OF THE INVENTION

The compounds of this invention are represented by the formula below ##STR2## wherein R³ is one of the groups A, B, or C ##STR3## R is hydrogen or lower alkyl, n is zero or the positive integer one, two, or three, each of R¹ and R² is alkyl, or taken together represent an alkylene, an alkenylene, an alkyl substituted alkylene, an alkylene ether, and alkyl substituted alkylene ether, or an alkyl substituted alkylene amine ring structure.

The compounds of this invention are useful as insect repellents and are particularly effective against many Dipteran.

The novel compounds of this invention are especially effective in repelling a wide variety of insects such as ticks, chiggers, cockroaches, and biting diptera such as mosquitoes, stable flies, deer flies, black flies, and sand flies. Certain novel amides reported in this invention are about equally as effective as deet against mosquitoes and are significantly more repellent than deet against other biting flies when tested on skin. The skin test is the obvious critical test when one considers personal protection; however, clothing repellents are also very important especially in areas of heavy mosquito infestations (The Journal of the American Medical Association, 196, 253, 1966). Certain amides of this invention provide exceptional protection against mosquitoes when applied to cloth.

The amides were synthesized as follows: the appropriate acid chloride was slowly added with stirring to an anhydrous ether solution of the amine cooled in an ice bath (either the amine itself or pyridine was used as a hydrochloric acid scavenger). The reaction mixture was allowed to warm to room temperature and then allowed to stand for several hours, usually overnight. The amides were isolated by routine extraction procedures and purified by distillation under high vacuum. Purity was checked by gas chromatographic analysis.

A typical procedure is illustrated by the following description of the synthesis of 1-(3-cyclohexenecarbonyl) piperidine, compound 20 in Table 1: 3-cyclohexenecarbonyl chloride, 28.9 grams (0.2 mole), was added dropwise to an ice cold solution (0°-10° C.) of piperidine, 34 grams (0.4 mole) in 250 ml of anhydrous ether. The solution was stirred vigorously during the addition. The reaction mixture was allowed to warm to room temperature and to stand overnight. Water was added to dissolve the precipitated piperidine hydrochloride salt. The organic layer was then washed sequentially with 5% hydrochloric acid and sodium bicarbonate solutions and finally with a saturated salt solution until the wash was neutral to litmus paper and dried over anhydrous magnesium sulfate. After filtering, the solvent was removed under reduced pressure (water pump). The crude amide was distilled under high vacuum to give 31.4 grams of product-b.p. 114°-15° C./0.2 mm Hg), n_(D) ²⁵ 1.5159.

The physical constants of the compounds are presented in Table 1.

The repellent activity of the amides of the present invention was demonstrated by practical laboratory and field tests against mosquitoes and a variety of other biting diptera. The effectiveness of the repellents was determined by directly comparing their repellency with that of deet in tests on skin and with dimethyl phthalate in tests on cloth.

In the following description of the testing procedures the first confirmed bite is defined as a bite followed by another within thirty minutes.

For the purposes of this invention, the compounds were tested as solutes in alcohol, acetone, or other volatile solvent. However, other compatible liquid or solid carriers may also be used.

TESTING PROCEDURES

STABLE FLIES.

The repellents were applied as 1-ml aliquots of a 25% ethanol solution and spread evenly over the forearm of a subject from wrist to elbow. Since the ethanol solution was formulated on a weight-volume basis, 250 mg of repellent was applied to the forearm in each test. The most promising compounds (those equal to or better than the deet standard at the 25% dosage) were then tested as 12.5% and 6.25% ethanol solutions.

The evaluations were carried out in an outdoor cage (103 cm square and 133 cm high) constructed of aluminum and having a solid top and bottom and screen wire on four sides. Four of the sides had port openings covered with 30.5-cm (12-in.) tubular cloth stockinettes. The centers of the ports were 30 cm from the bottom of the cage, which rested on a table 80 cm high. One arm each of up to four treated subjects at a time could be inserted through the ports into the cage.

Approximately 12,000 S. calcitrans pupae were placed in cups and allowed to emerge in the test cage over an 8-day period. The tests were started the 4th day, when approximately 8000 flies had emerged. The remaining 4000 that emerged over the next 4 days maintained a relatively stable population in respect to numbers and avidity. Citrated beef blood on a cotton pad was offered for 45 minutes each day after the repellent tests were completed. This short-term feeding period provided a small but adequate food intake, and avidity was not reduced as a result of complete engorgement. Results obtained when an untreated forearm was inserted into the test cage before and during the tests each day gave a measure of the avidity of the flies, though it was impossible to count the attacks on the untreated arm.

The effectiveness of each chemical was determined by the protection time; that is, the time between treatment and the first confirmed bite. Therefore, 30 minutes after the application of the test chemical and every 30 minutes thereafter, the treated arms were inserted into the test cage for 3 minutes unless bites occurred sooner.

Since test subjects differ in attractiveness and insects differ in avidity, the best measure of the effectiveness of a repellent is its ratio of protection time vs. that of a standard repellent used in similar conditions. Deet was the standard in all of the tests reported here. It was paired with each of the other candidate repellents in 10 different test series.

The experimental design used was a round-robin series in which each repellent was paired concurrently against another repellent on the arms of a subject. An adjusted average protection time that allowed for individual variation between test subjects and test conditions was then computed (Soap and Chemical Specialties, 33, 115-17 and 129-133, 1957).

BLACK FLIES.

The principal test site was in the vicinity of Kidney Pond, Baxter State Park, Maine. Meadows bordered by fast moving mountain streams and an abundance of wildlife provided optimum breeding conditions in this area. Several species of blackflies were represented in the population attacking four test subjects. Of these, the two most abundant were identified as Simulium venustum Say and Prosimulium mixtum Syme and Davis. Repellents were applied as 1-ml aliquots of a 12.5 or 25% ethanol solution and spread evenly over the forearm of a subject from wrist to elbow. The ethanol solution was formulated on a weight-volume basis, so either 125 or 250 mg of repellent was applied in each test.

Treated arms were continuously exposed to the natural populations of flies. Subjects intermittently moved about with arms raised or on hips, squatted, or sat down for brief periods of 5 to 10 minutes. These positions, coupled with slow walking and standing every few minutes, appeared to be attractive to black flies (Simulids and Prosimulids) and were used as standard procedure in all tests. Heat-nets and gloves were worn by the test subjects to prevent attack on exposed untreated parts of the body.

Two series of round-robin tests were conducted in the spring of 1977 using 12.5 or 25% solutions of repellent in ethanol; one series was conducted during June 1978 using a 25% solution of repellent in ethanol. The effectiveness of each chemical was determined by the protection time, i.e., the time between treatment and the first confirmed bite. Since test subjects differ in attractiveness and insects differ in avidity, the best measure of the effectiveness of a repellent is the ratio of its protection time to that of a standard repellent under similar conditions. Deet was the standard repellent in these tests.

In the round-robin test each repellent was paired with each other repellent on the arms of a subject (four or five replicates). An adjusted average protection time that allowed for individual variations between test subjects and test conditions was then computed. Black fly landing rates ranged from 14 to 40/minute during the test period.

DEER FLIES.

The compounds and the standard repellent, deet, were tested on the forearms of human subjects against natural populations of the deer fly, Chrysops atlanticus. The materials were formulated as 25% ethanol solutions and applied at the rate of 1 ml per forearm. The field tests were conducted along logging roads adjacent to the marshes of the Ogeechee River at Richmond Hill, Ga., where C. atlanticus populations occur in great numbers annually. Since the flies are attracted to motion, the test subjects continually walked while exposing their treated arms to the flies. The tests were terminated when a confirmed bite was received. The chemicals were evaluated in round-robin tests with five compounds and a deet standard in each series. During the 3-week test period the landing rate averaged 33 flies/man and ranged from 13 to 54/man.

SAND FLIES.

Two test sites were used, one at YankeeTown, Fla. on the Gulf coast and one at Parris Island, South Carolina. The repellents were applied as 25% solutions in ethanol on the forearms (wrist to elbow) of test subjects. Because of the limited period of insect activity (early morning or late afternoon to dusk) the subjects were pretreated 2 hours prior to the test period to effect aging of the repellents. The repellents were evaluated against the standard repellent, deet, in paired tests (3 replications). A test repellent was applied to one arm of a subject and deet to the other. Effectiveness was determined by the number of bites received during the test period. A control (no repellent treatment) was included in each test to ascertain the level of insect pressure.

MOSQUITOES.

Tests on skin.

For laboratory tests, 1 ml of a 25% ethanol solution of the repellent was spread evenly over the forearm of the subject. The treated forearms were exposed to about 1500 female laboratory reared Aedes aegypti or Anopheles quadrimaculatus mosquitoes in cages. Effectiveness was based on complete protection, that is, the time between treatment and the first confirmed bite. The effectiveness of the compounds was compared to that of the standard repellent, deet. The chemicals were tested in a round-robin series in a balanced incomplete block design in which each repellent in the series was paired against each other repellent in the series on opposite arms of a given number of subjects.

The field tests were conducted at sites adjacent to Mosquito Lagoon near New Smyrna Beach, Fla. The repellents were applied in the same manner as for the laboratory tests. The treated arms were exposed continuously to the natural population of mosquitoes until the first confirmed bite was received. Protective clothing and head nets were worn by the test subjects to protect against attack on exposed untreated parts of the body. The experimental design used was a balanced incomplete block as in the laboratory tests.

Tests on cloth.

Test materials were applied at the rate of 3.3 g of compound per 0.1 m² cloth to a measured portion (0.03 m²) of a cotton stocking as 10% solutions in acetone or other volatile solvent. After 2 hours, the treated stocking was placed over an untreated nylon stocking on the arm of a human subject and exposed for 1 minute in a cage containing about 1500 five- to eight-day old A. aegypti or A. quadrimaculatus. The test exposure was repeated at 24 hours and then at weekly intervals until five bites were received in 1 minute. Days to the first bite and to five bites were recorded. Between tests, the treated stockings were placed on a rack at room temperature, and evaporation was allowed to continue. A standard repellent, dimethyl phthalate, was tested concurrently and was effective for 11 to 21 days against both mosquito species.

The merits of the present invention are illustrated in the results shown in the tables.

The data in Table 2 show compounds 2, 7, 20, 33, 34, 47, and 49 were more active against the stable fly than the deet standard at all concentrations tested. Compounds 20 and 34 were significantly more effective than deet at all three dosages (0.05% level of confidence). Compounds 21 and 35 were more active than deet at two concentrations and equal to it at the lowest concentration tested. The repellent effect of certain of these chemicals was as much as 4.5× that of deet and provided protection up to 9 hours; the protection time of deet ranged from 2 to 3 hours. Data for compounds 4, 6, 17, 18, 19, 31, and 45 are shown to illustrate the unpredictability of repellent activity of closely related chemicals.

The data in Table 3 show all eight compounds and deet are very good black fly repellents. Compound 21 is significantly more effective than deet at the 25% dosage providing about 10.5 hours protection. There is no significant difference between the remaining compounds and deet at the 25% dosage. Although not significantly more effective than deet, the adjusted mean for compound 20 was 0.5 and 1.5 hours greater than that of deet at the two test dosages. Compounds 7 and 35 provided about 7 hours protection; compounds 20 and 47 provided over 8 hours protection; compounds 6 and 33 provided about 9 hours protection.

The data in Table 4 show 10 compounds that exceeded deet in repellency against deer flies. Compound 20 was significantly more effective than deet with an adjusted mean protection time of 6.3 hours.

The data in Table 5 show compounds 2, 7, 20, and 35 greatly superior to deet in tests conducted in Florida against the sand fly Culicoides mississippiensis. Compounds 2 and 20 were also superior to deet in the Parris Island tests against Culicoides hollensis. Deet is considered a good repellent for sand flies (Meditsinskaya Parazitologiya i Parazitarnye Bolezni, 35 (5), 549, 1963). A biting rate of about 5/hour would make the presence of sand flies tolerable to most people (Journal of Economic Entomology, 64 (1), 264, 1971). The data show certain compounds of this invention equalling or exceeding this criteria in one test and equalling or closely approaching it in the second test. The number of bites experienced by the check, clearly shows very high insect pressure during these tests, emphasizing the effectiveness of the repellents.

The data in Table 6 show the relative repellency of compounds of this invention against mosquitoes when applied to skin in laboratory and field tests. Deet is an excellent mosquito repellent (The Journal of the American Medical Association, 196, 253, 1966). Repellents 33 and 34 were about equally as effective against Aedes aegypti as deet; repellents 19, 20, 21, and 34 were about equally as effective against Anopheles quadrimaculatus as deet. In field tests, repellents 2 and 20 were 1.5 and 1.4 times as effective as deet against Aedes taeniorhynchus and 4, 6, 7, 21, 33, and 47 were about equally as effective as deet. Because deet is such an effective mosquito repellent, chemicals having 0.5 ratios to deet are considered good mosquito repellents.

The data in Table 7 show 91 of the repellents were more effective than the standard against one species of mosquito and 9 other compounds were about equally as effective as the standard. Repellents 91, 100, 101, and 115 provided outstanding protection of over 200 days and 29 other repellents provided exceptional protection of over 100 days against one species or the other. All chemicals providing 11 or more days protection are considered promising repellents.

The foregoing examples of repellent action of these novel amides against specific insect pests is meant to be illustrative rather than limiting. For example, the compounds of the present invention can be mixed with inert ingredients or with other known insect repellents. The compounds may also be formulated or embodied into repellent compositions in the form of creams, lotions, emulsions, suspensions, solutions, dusts, and aerosol or other type of sprays.

Although insect repellents are usually applied to the skin, the compounds of this invention and formulations containing them are also useful when applied to clothing, netting, packaging, shipping containers, animals, and growing plants.

                                      TABLE 1                                      __________________________________________________________________________     Physical constants of compounds synthesized in accordance with the             procedures of this invention                                                    No.                                                                               ##STR4##     or m.p. (°C.)B.p. (°C./mmHg)Physical                            constants                                                                                n.sub.D.sup.25                                                                     No.                                                                               ##STR5##      or m.p. (°C.)B.p.                                                      (°C./mmHg)Physical                                                      constants                                                                                n.sub.D.sup.25         __________________________________________________________________________      ##STR6##                                                                      1  N,N-Dimethylamino                                                                           69-70/0.45                                                                              1.4794                                                                             9  4-Methyl-1-piperidyl                                                                         113-14/0.8                                                                              1.4970                  2  N,N-Dipropylamino                                                                           93-5/0.45                                                                               1.4685                                                                             10 2-Ethyl-1-piperidyl                                                                          131/1.5  1.4970                  3  N,N-Dibutylamino                                                                            133/1.5  1.4675                                                                             11 2,6-Dimethyl-1-piperidyl                                                                     109-11/0.5                                                                              1.4950                  4  1-Pyrrolidyl 67-8         12 1,2,3,6-Tetrahydro-1-                                                                        107-9/0.5                                                                               1.5175                                                  pyridinyl                                      5  1-Piperidyl  108/0.45 1.5030                                                                             13 4-Methyl-1-piperazinyl                                                                       100-2/0.1                                                                               1.5041                  6  1-Hexahydro-1H-azepinyl                                                                     120/0.25 1.5038                                                                             14 4-Morpholinyl 57-8                             7  2-Methyl-1-piperidyl                                                                        110-13/0.7                                                                              1.5001                                                                             15 2.6-Dimethyl-4-morpholinyl                                                                   116-17/0.3                                                                              1.4919                  8  3-Methyl-1-piperidyl                                                                        114-16/0.45                                                                             1.4974                                                 ##STR7##                                                                      16 N,N-Dimethylamino                                                                           75-6/0.4 1.4960                                                                             24 4-Methyl-1-piperidyl                                                                         110-12/0.15                                                                             1.5087                  17 N,N-Dipropylamino                                                                           88/0.15  1.4804                                                                             25 2-Ethyl-1-piperidyl                                                                          114-15/0.1                                                                              1.5068                  18 N,N-Dibutylamino                                                                            103/0.1  1.4775                                                                             26 2.6-Dimethyl-1-piperidyl                                                                     112-13/0.1                                                                              1.5055                  19 1-Pyrrolidyl 44-5         27 1,2,3,6-Tetrahydro-1-                                                                        114-16/0.45                                                                             1.5315                                                  pyridinyl                                      20 1-Piperidyl  114-15/0.2                                                                              1.5159                                                                             28 4-Methyl-1-piperazinyl                                                                       112-14/0.1                                                                              1.5181                  21 1-Hexahydro-1H-azepinyl                                                                     105-6/0.15                                                                              1.5151                                                                             29 4-Morpholinyl 114-16/0.25                                                                             1.5194                  22 2-Methyl-1-piperidyl                                                                        110-12/0.1                                                                              1.5106                                                                             30 2,6-Dimethyl-4-morpholinyl                                                                   115-16/0.4                                                                              1.5043                  23 3-Methyl-1-piperidyl                                                                        108-10/0.1                                                                              1.5087                                                 ##STR8##                                                                      31 N,N-Dipropylamino                                                                           100/0.7  1.4682                                                                             38 4-Methyl-1-piperidyl                                                                         108/0.8  1.4908                  32 N,N-Dibutylamino                                                                            126/0.9  1.4669                                                                             39 2-Ethyl-1-piperidyl                                                                          175-8/18 1.4930                  33 1-Pyrrolidyl 95/0.25  1.4941                                                                             40 2.6-Dimethyl-1-piperidyl                                                                     108-10/0.5                                                                              1.4905                  34 1-Piperidyl  104-6/0.5                                                                               1.4970                                                                             41 1,2,3,6-Tetrahydro-1-                                                                        118-20/1.3                                                                              1.5100                                                  pyridinyl                                      35 1-Hexahydro-1H-azepinyl                                                                     115-18/0.9                                                                              1.5000                                                                             42 4-Methyl-1-piperazinyl                                                                       120-2/1.0                                                                               1.4990                  36 2-Methyl-1-piperidyl                                                                        141-3/0.25                                                                              1.4930                                                                             43 4-Morpholinyl 108-9/0.4                                                                               1.4975                  37 3-Methyl-1-piperidyl                                                                        168-70/18                                                                               1.4909                                                                             44 2,6-Dimethyl-4-morpholinyl                                                                   75-7                              ##STR9##                                                                      45 N,N-Dipropylamino                                                                           108/2.0  1.4794                                                                             52 4-Methyl-1-piperidyl                                                                         122-4/1.0                                                                               1.5020                  46 N,N-Dibutylamino                                                                            120/0.45 1.4765                                                                             53 2-Ethyl-1-piperidyl                                                                          116-18/0.5                                                                              1.5036                  47 1-Pyrrolidyl 133-6/0.2                                                                               1.5082                                                                             54 2.6-Dimethyl-1-piperidyl                                                                     115-17/0.5                                                                              1.5017                  48 1-Piperidyl  109/0.5  1.5090                                                                             55 1,2,3,6-Tetrahydro-1-                                                                        113-15/0.7                                                                              1.5234                                                  pyridinyl                                      49 1-Hexahydro-1H-azepinyl                                                                     135/0.9  1.5116                                                                             56 4-Methyl-1-piperazinyl                                                                       105-7/0.3                                                                               1.5106                  50 2-Methyl-1-piperidyl                                                                        120-2/1.1                                                                               1.5049                                                                             57 4-Morpholinyl 104-5/0.2                                                                               1.5115                  51 3-Methyl-1-piperidyl                                                                        120-2/1.3                                                                               1.5035                                                                             58 2,6-Dimethyl-4-morpholinyl                                                                   122-5/0.4                                                                               1.4990                   ##STR10##                                                                     59 N,N-Dipropylamino                                                                           93-5/0.2 1.4900                                                                             66 4-Methyl-1-piperidyl                                                                         98-100/0.1                                                                              1.5163                  60 N,N-Dibutylamino                                                                            100-2/0.1                                                                               1.4862                                                                             67 2-Ethyl-1-piperidyl                                                                          108-9/0.15                                                                              1.5168                  61 1-Pyrrolidyl 105-8/0.15                                                                              1.5262                                                                             68 2,6-Dimethyl-1-piperidyl                                                                     100-1/0.15                                                                              1.5166                  62 1-Piperidyl  111-13/0.2                                                                              1.5244                                                                             69 1,2,3,6-Tetrahydro-1-                                                                        110/0.1  1.5401                                                  pyridinyl                                      63 1-Hexahydro-1H-azepinyl                                                                     121-2/0.4                                                                               1.5262                                                                             70 4-Methyl-1-piperazinyl                                                                       103-4/0.1                                                                               1.5253                  64 2-Methyl-1-piperidyl                                                                        108-9/0.2                                                                               1.5197                                                                             71 4-Morpholinyl 99-100/0.1                                                                              1.5258                  65 3-Methyl-1-piperidyl                                                                        110-12/0.3                                                                              1.5169                                                                             72 2,6-Dimethyl-1-morpholinyl                                                                   100-2/0.1                                                                               1.5113                   ##STR11##                                                                     73 N,N-Dimethylamino                                                                           87-8/0.45                                                                               1.4780                                                                             81 4-Methyl-1-piperidyl                                                                         121/0.5  1.4935                  74 N,N-Dipropylamino                                                                           108-9/0.45                                                                              1.4708                                                                             82 2-Ethyl-1-piperidyl                                                                          122-4/0.2                                                                               1.4943                  75 N,N-Dibutylamino                                                                            139/0.75 1.4698                                                                             83 2,6-Dimethyl-1-piperidyl                                                                     121-3/0.3                                                                               1.4942                  76 1-Pyrrolidyl 110-12/0.25                                                                             1.4977                                                                             84 1,2,3,6-Tetrahydro-1-                                                                        122-4/0.15                                                                              1.5114                                                  pyridinyl                                      77 1-Piperidyl  109-11/0.2                                                                              1.5000                                                                             85 4-Methyl-1-piperazinyl                                                                       109/0.15 1.5016                  78 1-Hexahydro-1H-azepinyl                                                                     114-16/0.2                                                                              1.5019                                                                             86 4-Morpholinyl 68-70                            79 2-Methyl-1-piperidyl                                                                        105-7/0.2                                                                               1.4945                                                                             87 2,6-Dimethyl-4-morpholinyl                                                                   125-7/0.5                                                                               1.4892                  80 3-Methyl-1-piperidyl                                                                        118/0.4  1.4942                                                 ##STR12##                                                                     88 N,N-Dimethylamino                                                                           100-2/0.4                                                                               1.4782                                                                             96 4-Methyl-1-piperidyl                                                                         136-7/0.5                                                                               1.4919                  89 N,N-Dipropylamino                                                                           117-18/0.45                                                                             1.4715                                                                             97 2-Ethyl-1-piperidyl                                                                          126-7/0.1                                                                               1.4938                  90 N,N-Dibutylamino                                                                            133-5/0.4                                                                               1.4701                                                                             98 2,6-Dimethyl-1-piperidyl                                                                     135/0.35 1.4895                  91 1-Pyrrolidyl 126-7/0.2                                                                               1.4928                                                                             99 1,2,3,6-Tetrahydro-1-                                                                        134-5/0.5                                                                               1.5070                                                  pyridinyl                                      92 1-Piperidyl  129-31/0.2                                                                              1.4950                                                                             100                                                                               4-Methyl-1-piperazinyl                                                                       139- 40/0.1                                                                             1.4966                  93 1-Hexahydro-1H-azepinyl                                                                     131-4/0.3                                                                               1.4985                                                                             101                                                                               4-Morpholinyl 122-4/0.1                                                                               1.4961                  94 2-Methyl-1-piperidyl                                                                        128-30/0.35                                                                             1.4933                                                                             102                                                                               2,6-Dimethyl-4-morpholinyl                                                                   123-5/0.1                                                                               1.4876                  95 3-Methyl-1-piperidyl                                                                        136-8/0.5                                                                               1.4912                                                 ##STR13##                                                                     103                                                                               N,N-Dimethylamino                                                                           109-10/0.4                                                                              1.4764                                                                             111                                                                               4-Methyl-1-piperidyl                                                                         145-7/0.45                                                                              1.4875                  104                                                                               N,N-Dipropylamino                                                                           128-30/0.4                                                                              1.4712                                                                             112                                                                               2-Ethyl-1-piperidyl                                                                          145/0.25 1.4910                  105                                                                               N,N-Dibutylamino                                                                            148/0.4  1.4705                                                                             113                                                                               2,6-Dimethyl-1-piperidyl                                                                     151-3/0.5                                                                               1.4874                  106                                                                               1-Pyrrolidyl 137-9/0.4                                                                               1.4905                                                                             114                                                                               1,2,3,6-Tetrahydro-1-                                                                        145-6/0.45                                                                              1.5035                                                  pyridinyl                                      107                                                                               1-Piperidyl  139-40/0.5                                                                              1.4920                                                                             115                                                                               4-Methyl-1-piperazinyl                                                                       134-5/0.15                                                                              1.4975                  108                                                                               1-Hexahydro-1H-azepinyl                                                                     153-4/0.5                                                                               1.4940                                                                             116                                                                               4-Morpholinyl 149-51/0.45                                                                             1.4932                  109                                                                               2-Methyl-1-piperidyl                                                                        142-3/0.45                                                                              1.4909                                                                             117                                                                               2,6-Dimethyl-4-morpholinyl                                                                   145-7/0.45                                                                              1.4828                  110                                                                               3-Methyl-1-piperidyl                                                                        143-5/0.5                                                                               1.4882                                                __________________________________________________________________________

                  TABLE 2                                                          ______________________________________                                         Repellency of compounds to the stable fly Stomoxyx                             calcitrans when applied to the skin at various concentrations                  in ethanol and compared to deet as a test standard                                     Protection time                                                                (minutes)                                                                   %                  Adjusted                                                                               Ratio to                                                                               No. of                                 No.  Conc.    Range     mean    deet.sup.a                                                                             tests                                  ______________________________________                                         2    6.25     30-90     55      1.7     3                                           12.5     300-360   315     4.50.sup.b                                                                             5                                           25.0     210-463   321     2.02.sup.b                                                                             5                                      4    25.0      30-270   103     0.4     5                                      6    25.0      30-268   183     0.71    5                                      7    25.0     120-300   246     2.01.sup.b                                                                             4                                      17   25.0     180-360   225     0.85    5                                      18   25.0      30-189   122     0.46    5                                      19   25.0      90-420   237     1.0     5                                      20   6.25      30-120   103     2.5.sup.b                                                                              3                                           12.5      60-240   128     2.4.sup.b                                                                              4                                           25.0     360-390   387     2.39.sup.b                                                                             5                                      21   6.25     30-60     33      1.0     5                                           12.5     270-450   306     1.42    5                                           25.0     300-510   457     3.78.sup.b                                                                             4                                      31   25.0     30-60     36      0.2     5                                      33   6.25      60-180   80      1.6     3                                           12.5      90-210   150     3.3.sup.b                                                                              4                                           25.0     240-270   266     1.6     4                                      34   6.25      30-120   118     2.4.sup.b                                                                              3                                           12.5     270-330   320     4.57.sup.b                                                                             5                                           25.0     390-510   419     2.6.sup.b                                                                              4                                      35   6.25     30-30     30      1.0     5                                           12.5     210-375   326     3.27.sup.b                                                                             5                                           25.0     390-510   459     2.9.sup.b                                                                              4                                      36   25.0      30-120   101     1.43    5                                      45   25.0      30-180   78      0.44    5                                      47   6.25     30-90 63  1.9     3                                                   12.5     120-270   230     3.29.sup.b                                                                             5                                           25.0     150-405   264     1.66    5                                      49   6.25     30-60     38      1.15    5                                           12.5     150-330   306     1.42    5                                           25.0     480-510   538     3.02.sup.b                                                                             5                                      50   25.0      60-150   125     1.41    5                                      ______________________________________                                          .sup.a Data compiled from a number of different tests, accounting for the      fluctuation between protection time and ratio to deet among the members o      the series.                                                                    .sup.b Significantly different from deet at the 0.05% level of confidence

                  TABLE 3                                                          ______________________________________                                         Repellency of compounds applied to the skin as 12.5 and/or                     25% ethanol solutions compared with deet against                               blackflies in two series of field tests                                                  Protection time (min)                                                        %                Adjusted Ratio to                                                                              No. of                                No.     Conc.   Range    mean     deet   tests                                 ______________________________________                                         Test I (1977)                                                                  Deet (Std)                                                                             12.5    145-283  161      1.00   5                                             25.0    287-511  426      1.00   4                                     20      12.5    123-314  193      1.20.sup.a                                                                            5                                             25.0    413-565  505      1.19.sup.a                                                                            4                                      7      12.5     26-222  95       0.59   5                                             25.0    309-515  424      1.00.sup.a                                                                            4                                     35      12.5     24-126  93       0.58   5                                             25.0    342-542  412      0.97.sup.a                                                                            4                                      2      12.5     25-112  71       0.44   5                                             25.0    198-375  314      0.74.sup.a                                                                            4                                     Test II (1978)                                                                 Deet (Std)                                                                             25.0    399-623  520      1.00   5                                      6      25.0    411-628  537      1.03.sup.a                                                                            5                                     21      25.0    524-725  632      1.21.sup.b                                                                            5                                     33      25.0    498-603  554      1.07.sup.a                                                                            5                                     47      25.0    425-649  486      0.94.sup.a                                                                            5                                     ______________________________________                                          .sup.a Not significantly different from deet at the 0.05% level of             confidence.                                                                    .sup.b Significantly different from deet at the 0.05% level of confidence

                  TABLE 4                                                          ______________________________________                                         Repellency of compounds applied to the skin as                                 25% ethanol solutions and compared with deet against                           deerflies in field tests (Avg. of 5 tests)                                     Protection time (min)    Ratio to                                              No.     Range      Adjusted mean deet.sup.a                                    ______________________________________                                         2        10-178    133           3.00                                          4        4-77      23            0.51                                          6        10-173    75            1.69                                          17       15-143    62            1.39                                          18       6-36      40            0.89                                          20      363-421    380           5.83.sup.b                                    21       91-203    91            1.1                                           31      10-44      45            0.62                                          34       20-408    141           1.8                                           35       42-182    119           1.5                                           36       5-17      15            0.94                                          45       4-110     18            0.24                                          47       40-160    138           1.89                                          49       37-244    129           1.76                                          50       8-138     27            1.11                                          ______________________________________                                          .sup.a Data compiled from a number of tests, accounting for the                fluctuation between the protection time and ratio to deet among the            members of the series.                                                         .sup.b Significantly different from deet at the 0.05% level of confidence

                  TABLE 5                                                          ______________________________________                                         Repellency of compounds applied to the skin                                    as 25% ethanol solutions and compared with deet                                against the sandflies Culicoides mississippiensis                              and Culicoides hollensis in field tests                                        Compounds     Average     Average                                              paired        bites/test  bites/hour                                           ______________________________________                                         Tests at Yankee Town, Fla. (Avg. 3 tests)                                      Deet          29.0        19.2                                                 2             3.33        2.4                                                  Deet          31.67       21.0                                                 20            5.0         3.6                                                  Deet          106.0       70.8                                                 35            6.67        4.2                                                  Deet          45.0        30.0                                                 7             10.0        6.6                                                  Check         1299        865.8                                                Tests at Parris Island, S. C. (Avg. 3 tests)                                   Deet          28.67       18.6                                                 20            9.33        6.0                                                  Deet          85.0        54.6                                                 2             16.33       10.8                                                 Deet          12.0        7.8                                                  7             16.67       10.8                                                 Check         1566        1277.4                                               ______________________________________                                    

                  TABLE 6                                                          ______________________________________                                         Repellency of compounds to mosquitoes when applied                             to the skin as 25% ethanol solutions                                           Ratio to deet                                                                  Laboratory test         Field test                                                    Aedes      Anopheles     Aedes                                          No.    aegypti    quadrimaculatus                                                                              taeniorhynchus                                 ______________________________________                                          2     0.22       0.28          1.5                                             4     0.22       0.11          0.77                                            6     0.14       0.74          0.82                                            7     0.70       0.11          1.15                                           17     0.24       0.33          0.52                                           18     0.13       0.05          0.07                                           19     0.20       0.73          0.44                                           20     0.68       1.0           1.4                                            21     0.64       0.86          0.7                                            31     0.24       0.08          0.45                                           33     1.12       0.86          0.69                                           34     0.89       1.0           0.34                                           45     0.23       0.11          0.12                                           47     0.28       0.24          0.99                                           49     0.55       0.09          0.65                                           ______________________________________                                    

                  TABLE 7                                                          ______________________________________                                         Repellency of compounds to mosquitoes in tests on cloth                        Aedes aegypti     Anopheles quadrimaculatus                                    Days to           Days to                                                      No.   1st bite  5 bites   1st bite  5 bites                                    ______________________________________                                          2    15        15        8         8                                          4     30        38        38        79                                         5     30        38        30        30                                         6     106       113       22        38                                         7     104       104       111       111                                        8     104       104       22        22                                         9     52        104       0         22                                         10    104       104       1         22                                         11    104       104       1         37                                         12    15        15        15        15                                         13    7         15        7         111                                        14    0         1         27        27                                         15    15        28        35        35                                         17    15        15        15        15                                         18    0         30        0         1                                          19    28        28        70        94                                         20    21        28        28        48                                         21    64        87        70        70                                         22    69        69        83        83                                         23    36        36        36        51                                         24    20        20        83        83                                         25    83        83        83        83                                         26    36        36        36        36                                         27    36        36        63        63                                         28    28        28        63        83                                         29    0         0         35        35                                         30    8         8         22        22                                         31    15        15        1         1                                          33    21        28        28        28                                         34    21        28        13        13                                         35    28        28        6         6                                          36    23        43        0         0                                          37    23        51        0         0                                          38    36        36        21        21                                         39    51        71        0         0                                          40    1         23        0         0                                          41    8         15        8         8                                          42    1         1         36        50                                         43    36        77        64        71                                         44    28        28        15        15                                         45    27        27        1         1                                          47    27        27        1         1                                          48    33        41        1         1                                          49    27        47        1         1                                          50    23        51        0         23                                         51    36        36        0         21                                         52    36        36        8         36                                         55    15        15        0         1                                          57    8         22        36        105                                        58    1         28        22        22                                         59    1         35        49        49                                         61    34        55        28        28                                         62    70        70        70        91                                         63    70        128       0         111                                        64    70        70        0         76                                         65    35        70        0         49                                         66    70        70        0         77                                         67    21        34        47        47                                         68    1         28        20        20                                         69    28        28        20        20                                         70    28        28        47        47                                         71    0         0         47        47                                         72    0         34        20        190                                        74    0         0         28        28                                         76    108       108       21        119                                        77    28        108       28        28                                         78    21        130       1         8                                          79    28        102       0         0                                          80    28        102       0         0                                          81    28        51        8         8                                          82    0         28        8         8                                          83    101       108       108       108                                        84    8         28        28        28                                         85    0         105       134       175                                        86    0         1         1         18                                         87    0         105       126       126                                        88    21        21        24        24                                         91    169       169       238       238                                        92    29        29        7         182                                        93    21        65        21        44                                         94    7         21        1         1                                          95    7         21        1         126                                        97    0         12        0         12                                         98    0         21        126       126                                        99    0         12        0         93                                         100   7         7         21        268                                        101   61        133       238       238                                        102   61        93        133       133                                        103   42        42        24        54                                         106   61        160       160       160                                        107   0         36        36        36                                         108   22        22        36        134                                        110   0         1         36        36                                         111   0         0         52        94                                         112   13        13        36        104                                        113   0         1         134       134                                        114   0         36        134       134                                        115   0         51        310       318+                                       116   77        134       134       134                                        117   22        22        134       134                                        ______________________________________                                          +Compound still in test.                                                  

We claim:
 1. In an insect repellent composition containing an insect repelling effective amount of an active ingredient and a carrier, the improvement wherein said active ingredient is selected from the group consisting of(a) a compound of the, formula ##STR14## wherein R³ is one of the groups, A, B, or C ##STR15## R is hydrogen or lower alkyl, n the positive integer one, two, or three, and R¹ and R² together with the N is selected from the group consisting of 1-piperidyl, 2-methyl-1-piperidyl, 3-methyl-1-piperidyl, 4-methyl-1-piperidyl, 2-ethyl-1-piperidyl, and 2,6-dimethyl-1-piperidyl; (b) a compound of the formula ##STR16## wherein R¹ and R² taken together with the N is 2-methyl-1-piperidyl, 3-methyl-1-piperidyl, 4-methyl-1-piperidyl, 2-ethyl-1-piperidyl or 2,6-dimethyl-1-piperidyl.
 2. An insect repellent composition according to claim 1 wherein the R³ substituent in the active ingredient is ##STR17##
 3. An insect repellent composition according to claim 2 wherein R is hydrogen and n is one, two, or three.
 4. An insect repellent composition according to claim 1 wherein the R³ substituent in the active ingredient is ##STR18##
 5. An insect repellent composition according to claim 1 wherein the R³ substituent in the active ingredient is ##STR19##
 6. An insect repellent composition according to claim 5 wherein R¹ and R² taken together with the N is 1-piperidyl.
 7. A compound of the formula ##STR20## wherein R lower alkyl, and R¹ and R² taken together with the N is 1-piperidyl. 